Primary Focal Segmental Glomerulosclerosis (FSGS) is a proteinuric glomerular disease that affects podocyte function and survival and results in a typical pattern of histopathological injury including glomerulosclerosis on kidney biopsy [1, 2].
Renal transplant patients with primary FSGS or native FSGS face a high risk of recurrence of FSGS (recurrent FSGS, rFSGS) in the allograft (20 to 40% after a first transplant and up to 80% for re-transplantation) [3, 4]. Recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation leads to graft loss and has a potentially detrimental course toward the loss of renal function.
Native FSGS (nFSGS) can develop from a variety of causes, including genetic, toxicity, or for example from minimal change disease, a kidney disorder that can lead to nephrotic syndrome, although the nephrons of the kidney look normal under a regular microscope. Native FSGS can also develop from other proteinuric kidney diseases.
Immuneadsorption alleviates renal graft dysfunction in some cases and suggests implication of circulating antibodies as a potential culprit of the disease. Clinical association studies [5, 6] and animal and cell studies have identified elevated pre and post-transplantation serum levels of the soluble urokinase receptor (suPAR) [7, 8] as an altered in native and recurrent FSGS [7]. SuPAR levels, though correlative with FSGS recurrence [7, 8], may be non-specific and have been found elevated in other conditions such as sepsis.
Circulating permeability factors and auto-antibodies (autoantibody), such as anti-actin, anti-ATP synthase, and anti-nephrin [9-11] have been implicated in the pathogenesis of rFSGS. It was suggested that autoantibody participate in the pathogenesis of rFSGS, as autoantibody directed against podocyte tyrosine phosphatase receptor-O, nephrin or anti-Thy1.1[12, 13], when injected in animal models, can cause an increase in glomerular permeability, and rFSGS can be improved in some cases by manipulation of the humoral response by plasmapheresis and rituximab [14-17].
Observations notwithstanding, improvements in pre-transplant risk stratification for rFSGS, nFSGS, minimal change disease, and other proteinuric kidney diseases and subsequent treatment remain a major clinical challenge. The present invention provides compositions and methods for pre-transplant biomarkers of these diseases and appropriate treatment paradigms.